Chondroitin Sulfate Iron Colloid Research Articles

Reduction of recombinant human erythropoietin maintenance dose by supplementation with a low-dose iron preparation, given intravenously

Background. In chronic hemodialysis patients who showed iron deficiency, we investigated whether the maintenance dose of recombinant human erythropoietin (rHuEPO) could be reduced by long-term intravenous supplementation with a low-dose iron preparation. Methods. In 26 chronic hemodialysis patients who were receiving treatment with a maintenance dose of rHuEPO, without an iron supplement, who showed iron deficiency, the intravenous administration of 40 mg of chondroitin sulfate-iron colloid once per week after dialysis was initiated. We observed the patients' course for 1 year and investigated the reduction in the rHuEPO dose. Results. In the 26 patients, the rHuEPO dose was reduced by 25% after 6 months, and the reduction increased to 32% in the twelfth month. The patients were divided, according to the maintenance dose of rHuEPO received before the iron supplementation into high-, intermediate-, and low-dose groups (9000, 4500, and 2250 IU/week, respectively), and the results were analyzed. A marked reduction of the rHuEPO dose, of 46% in the twelfth month, was obtained in the intermediate-dose group. In the high- and low-dose groups, the reductions of the rHuEPO dose were low. Conclusions. In chronic hemodialysis patients with iron deficiency who are being treated with a maintenance dose of rHuEPO, the intravenous administration of a low dose of iron (40 mg/week) led to a reduction in the rHuEPO dose. This effect was marked in patients in the intermediate-dose rHuEPO group, i.e., 4500 IU/week, which is the most frequently employed maintenance dose in Japan. This therapeutic method can be recommended from a health-care economics perspective.

Pathomorphological study of Kupffer cells in hepatocellular carcinoma and hyperplastic nodular lesions in the liver

A pathomorphological study was conducted to clarify the localization of Kupffer cells in hepatocellular carcinoma (HCC) tissues and such hyperplastic nodular lesions as adenomatous hyperplasia (AH) and focal nodular hyperplasia (FNH). Materials were surgical specimens of 50 HCCs, 7 AHs, and 13 FNHs. These tissues were immunohistochemically stained with an anti-human macrophage antibody (anti-CD68 antibody). Among CD68-positive cells, short spindle-shaped cells were considered as Kupffer cells, and Kupffer cell numbers in tumor lesions and surrounding liver tissues of each specimen were comparatively examined. As a result, the number of Kupffer cells in well-differentiated HCC tissues less than 1 cm in diameter was 27.8 +/- 3.3 (mean +/- SE/0.25 mm2); in noncancerous tissues, it was 30.2 +/- 3.2, showing no statistically significant differences. The number of Kupffer cells in cancerous tissues decreased in comparison with the number in noncancerous tissues, as the tumor size increased and histological grade decreased. In hyperplastic nodular lesions, the number was higher in nodular lesions than in the surrounding liver tissues in 4 of 7 AHs (57.1%) and 6 of 13 FNHs (46.2%). This could explain the reason why enhanced MRI, which utilizes the selective taken-up mechanism of chondroitin sulfate iron colloid and superparamagnetic iron oxide into the reticuloendothelial system of the liver and spleen, depicts well- differentiated HCC and AH at the same signal intensity as in the surrounding liver tissues. Our findings also indicate that there is a limitation in differentiating or diagnosing small HCC and hyperplastic nodular lesions by using enhanced MRI, which utilizes Kupffer cell functions. (Hepatology 1996 Oct;24(4):807-12)

Dual contrast magnetic resonance imaging with combined use of positive and negative contrast agent in human hepatocellular carcinoma

Dual contrast magnetic resonance imaging (DCMR) with combined use of a negative contrast medium, chondroitin sulfate iron colloid (CSIC), and a positive contrast medium, Gd-DTPA, was attempted in 20 cases of hepatocellular carcinoma. Spin echo T1 weighted and T2 weighted images (T1WI, T2WI), and T1 weighted images 15 min after intravenous injection of Gd-DTPA (0.1 mmol kg-1) were obtained. Within 1 week, these MR studies were repeated within 1 h of intravenous injection of CSIC (23.6 mumol Fe kg-1) under similar conditions. DCMR and the other five imaging techniques were visually evaluated and compared in terms of tumour detectability, tumour spread and qualification of tumours (depiction of inner structure). DCMR was significantly better than Gd-DTPA enhanced T1WI in tumour detectability, and better than Gd-DTPA enhanced T1WI or CSIC enhanced T1WI in depicting tumour spread. In the qualification of tumours, DCMR was significantly better than all the other five imaging techniques. None of the patients in this study showed adverse reactions or significant changes in biochemistry. DCMR is an imaging technique which is able to utilize the characteristics of these contrast agents collectively, and exhibits advantages in grasping the inner structure of tumours, especially in hepatocellular carcinoma.

Correlation between Chondroitin Sulfate Iron Colloid-Enhanced MR Imaging and the Histological Grade of Hepatocellular Carcinoma

The association between contrast enhancement by chondroitin sulfate iron colloid (CSIC) and the histological grade of hepatocellular carcinoma (HCC) was evaluated in 24 patients diagnosed by histological examination of surgical specimens (26 nodules: 11 well-differentiated and 15 poorly-moderately-differentiated nodules). In the well-differentiated HCC nodules, the tumor-liver contrast to noise ratio (CNR) was not significantly increased after i.v. CSIC injection on both T1-weighted and T2-weighted images. In the moderately-poorly-differentiated HCC, CNR was significantly increased after CSIC administration on both T1-weighted and T2-weighted images (p < 0.01). MR imaging using CSIC may be useful for diagnosing the degree of HCC differentiation.

Receptor-Mediated Clearance of Chondroitin Sulfate Iron Colloid in the Rat Liver.

Our previous study demonstrated that reticuloendothelial system function can be monitored by in vivo clearance of chondroitin sulfate iron colloid [Ishida, H. et al. (1991): J. Biochem. Biophys. Methods; Ishida, H. et al (1992): J. Biochem. Biophys. Methods; Tsujinaka, T. et al. (1993): JPEN]. In the present study hepatic clearance of radiolabeled chondroitin sulfate iron colloid (CS59Fe) was investigated in detail. When administered intravenously, CS59Fe was taken up by not only Kupffer cells but also liver endothelial cells and liver parenchymal cells. Radioactivity per 106 cells was highest in Kupffer cells. When binding of CS59Fe to isolated liver cells was examined at 4°C, the association of CS59Fe showed a good linearity on a double-reciprocal plot, giving Nr (number of receptors) and Kp (membrane-particle constant). Nr was greatest of all for Kupffer cells. When CS59Fe was pretreated with plasma, the Nr increased and Kp decreased in Kupffer cells and liver endothelial cells, whereas Kp increased in liver parenchymal cells. However, no influence was found as a result of pre-treatment of CS59Fe with fibronectin or heated plasma. The addition of mannan had no effect. This in vitro chondroitin sulfate iron colloid binding assay may be useful to evaluate effects of various mediators on phagocytosis of hepatic cells.

Double Contrast MR Imaging with Iron Colloid and Gd-DTPA in Cholangiocellular Carcinoma

Double contrast MR imaging with combined use of chondroitin sulfate iron colloid (CSIC) and Gd-DTPA was attempted in 3 cases of cholangiocellular carcinoma (CCC). In all cases, nonenhanced spin echo T1- and T2-weighted images, and T1-weighted images after i.v. injection of Gd-DTPA were obtained. Within one week, the MR sequences were repeated one hour after i.v. injection of CSIC. Double contrast (CSIC/Gd-DTPA) T1-weighted imaging was evaluated and compared with the other sequences in terms of tumor detectability, tumor spreading and tumor characterization. Double contrast MR imaging was comparable in tumor detectability and superior as to the evaluation of spreading and characterization to the other MR imaging modalities.

Chondroitin Sulfate Iron Colloid-Enhanced MR Imaging in Patients with Hepatocellular Carcinoma

Chondroitin sulfate iron colloid (CSIC) was used as an MR contrast agent for the detection of hepatocellular carcinoma (HCC). The findings of 25 surgically confirmed HCCs in 19 patients were retrospectively analyzed. T1-, T2- and proton density-weighted spin echo MR images were obtained before and after i.v. injection of 23.6 μM Fe/kg of CSIC. Unenhanced and CSIC-enhanced MR images and images obtained by CT during arterial portography (CT-AP) were correlated with surgical pathology findings. The sensitivities of CSIC-enhanced and unenhanced MR imaging, and CT-AP were 92%, 80%, and 88%, respectively. No significant differences were noted. Portal flow abnormalities demonstrated by CT-AP did not affect the detection of HCC by CSIC-enhanced MR imaging. CSIC-enhancement at MR imaging was a disadvantage in the detection of lesions less than 1 cm in diameter. CSIC-enhanced MR imaging is a supplemental method for the detection of HCC.

Chondroitin Sulfate Iron Colloid-Enhanced MR Imaging in Patients with Hepatocellular Carcinoma

Chondroitin sulfate iron colloid (CSIC) was used as an MR contrast agent for the detection of hepatocellular carcinoma (HCC). The findings of 25 surgically confirmed HCCs in 19 patients were retrospectively analyzed. T1-, T2- and proton density-weighted spin echo MR images were obtained before and after i.v. injection of 23.6 μM Fe/kg of CSIC. Unenhanced and CSIC-enhanced MR images and images obtained by CT during arterial portography (CT-AP) were correlated with surgical pathology findings. The sensitivities of CSIC-enhanced and unenhanced MR imaging, and CT-AP were 92%, 80%, and 88%, respectively. No significant differences were noted. Portal flow abnormalities demonstrated by CT-AP did not affect the detection of HCC by CSIC-enhanced MR imaging. CSIC-enhancement at MR imaging was a disadvantage in the detection of lesions less than 1 cm in diameter. CSIC-enhanced MR imaging is a supplemental method for the detection of HCC.

Chondroitin sulfate iron colloid as MR contrast agent in differentiation between hepatocellular carcinoma and adenomatous hyperplasia : Suto Y, Kato T, Matsuo T, et al. (Department of Radiology, Tottori University Medical School, 36-1 Nishimachi, Yonago 683, Japan). Arta Radiol 1993;34:226–229

Chondroitin sulfate iron colloid as MR contrast agent in differentiation between hepatocellular carcinoma and adenomatous hyperplasia : Suto Y, Kato T, Matsuo T, et al. (Department of Radiology, Tottori University Medical School, 36-1 Nishimachi, Yonago 683, Japan). Arta Radiol 1993;34:226–229

Chondroitin Sulfate Iron Colloid-Enhanced MR Imaging in Patients with Hepatocellular Carcinoma

Chondroitin sulfate iron colloid (CSIC) was used as an MR contrast agent for the detection of hepatocellular carcinoma (HCC). The findings of 25 surgically confirmed HCCs in 19 patients were retrospectively analyzed. T1-, T2- and proton density-weighted spin echo MR images were obtained before and after i.v. injection of 23.6 microM Fe/kg of CSIC. Unenhanced and CSIC-enhanced MR images and images obtained by CT during arterial portography (CT-AP) were correlated with surgical pathology findings. The sensitivities of CSIC-enhanced and unenhanced MR imaging, and CT-AP were 92%, 80%, and 88%, respectively. No significant differences were noted. Portal flow abnormalities demonstrated by CT-AP did not affect the detection of HCC by CSIC-enhanced MR imaging. CSIC-enhancement at MR imaging was a disadvantage in the detection of lesions less than 1 cm in diameter. CSIC-enhanced MR imaging is a supplemental method for the detection of HCC.

コンドロイチン硫酸鉄コロイド併用肝ＭＲＩによる肝細胞癌の網内系機能評価と血流動態の対比

コンドロイチン硫酸鉄コロイド併用肝ＭＲＩによる肝細胞癌の網内系機能評価と血流動態の対比

Initial experiences of chondroitin sulfate iron colloid-enhanced MR imaging in patients with hepatocellular carcinoma: comparative study with CT during arterial portography

Abstract Chondroitin sulfate iron colloid (CSIC), a stable iron colloid preparation, is used for the treatment of iron deficiency anemia in Japan. CSIC administered intravenously accumulates in reticuloendothelial cells and reduces the signal intensity of the liver at magnetic resonance imaging (MRI) because of its T2*-shortening effect. Accordingly, CSIC produces a contrast between normal liver tissue and hepatocellular carcinoma (HCC) which has diminished reticuloendothelial function, enabling improved detection of HCC by MRI. In this study, we compared CSIC-enhanced MRI with computed tomography during arterial portography (CT AP), which is considered the most reliable imaging modality to detect HCC. Of 20 HCCs pathologically confirmed in 16 patients, 18 (90%) were detectable with CT-AP. Sixteen HCCs (80%) were detectable with unenhanced MRI. After the administration of CSIC, 18 (90%) could be detected. CSIC-enhanced MRI was found to be superior to CT-AP in the detection of HCCs in patients with portal flow abnormalities, i.e., porto-systemic shunting, laminal flow of contrast material and wedge-shaped perfusion defect. In contrast, CT-AP was found to be superior to CSIC-enhanced MRI in detecting HCCs of less than 1 cm in diameter. We consider that these imaging procedures are complementary to each other, and their combined use is the most reliable method by which to detect HCC.

Chondroitin sulfate iron colloid as an MR contrast agent for the hepatic reticuloendothelial system.

Chondroitin sulfate iron colloid (CSI), a therapeutic agent for asiderotic anemia, is widely used in the clinical field, and its safety has been established in Japan. We studied the potential of this agent for MRI of the hepatic reticuloendothelial system. Chondroitin sulfate iron colloid has a paramagnetic trivalent iron ion and is effective in shortening T2 relaxation time because it is taken up rapidly in the hepatic reticuloendothelial system after intravenous injection. Hepatic MR images were obtained before and 1 h after the intravenous injection of 26.9 mumol Fe/kg of CSI in rats with experimentally induced tumors and of 18-30 mumol Fe/kg in human subjects. The signal intensities of normal hepatic tissue were decreased in all cases, whereas those of tumors were unchanged after CSI injection in these two series. Consequently, good contrast was observed in each pulse sequence. Therefore, CSI seems to be clinically useful as a contrast agent for hepatic MRI.

Chondroitin Sulfate Iron Colloid as MR Contrast Agent in Differentiation between Hepatocellular Carcinoma and Adenomatous Hyperplasia

Using a 1.5 T MR imaging unit, T1- and T2-weighted images were obtained before and after i.v. administration of chondroitin sulfate iron colloid (CSIC) in order to differentiate hepatocellular carcinoma (n = 20) from adenomatous hyperplasia without atypia (n = 16). Differentiation was made from the tumor-liver contrast to noise ratio (CNR) and visual evaluation of the nodule, with reference to signal intensity relative to that of the surrounding liver. The CNR of adenomatous hyperplasia was on T1-weighted images significantly decreased after CSIC administration (p &lt; 0.01). On T2-weighted images, there was no significant difference in CNR after CSIC administration. On the other hand, the CNR of hepatocellular carcinoma was significantly increased after CSIC administration on both T1- and T2-weighted images (p &lt; 0.01). CSIC reflects intratumor reticuloendothelial cellular functions, and is therefore useful in differentiating hepatocellular carcinoma from adenomatous hyperplasia without atypia.

Chondroitin sulfate iron colloid as MR contrast agent in differentiation between hepatocellular carcinoma and adenomatous hyperplasia.

Using a 1.5 T MR imaging unit, T1- and T2-weighted images were obtained before and after i.v. administration of chondroitin sulfate iron colloid (CSIC) in order to differentiate hepatocellular carcinoma (n = 20) from adenomatous hyperplasia without atypia (n = 16). Differentiation was made from the tumor-liver contrast to noise ratio (CNR) and visual evaluation of the nodule, with reference to signal intensity relative to that of the surrounding liver. The CNR of adenomatous hyperplasia was on T1-weighted images significantly decreased after CSIC administration (p < 0.01). On T2-weighted images, there was no significant difference in CNR after CSIC administration. On the other hand, the CNR of hepatocellular carcinoma was significantly increased after CSIC administration on both T1- and T2-weighted images (p < 0.01). CSIC reflects intratumor reticuloendothelial cellular functions, and is therefore useful in differentiating hepatocellular carcinoma from adenomatous hyperplasia without atypia.

コンドロイチン硫酸鉄コロイド併用ＭＲＩと経動脈性門脈造影下ＣＴの肝細胞癌検出能の比較検討

コンドロイチン硫酸鉄コロイド併用ＭＲＩと経動脈性門脈造影下ＣＴの肝細胞癌検出能の比較検討

Dynamic change of reticuloendothelial system function after surgical stress.

The influence of surgical stress on the function of the reticuloendothelial system (RES) is not well elucidated. Because we established an in vivo functional test for the RES by using chondroitin sulfate iron colloid in rabbits, the normal range of RES function in healthy volunteers (n = 12) and the dynamic change of RES function in surgical patients after distal gastrectomy (n = 14) were examined by this method. In healthy volunteers, the maximum phagocytic velocity and membrane-particle constant were 0.0310 +/- 0.0052 mg/kg per minute and 0.575 +/- 0.205 mg/kg, respectively. In surgical patients, maximum phagocytic velocity (postoperative day 1, 0.0408 +/- 0.0088; postoperative day 3, 0.0486 +/- 0.0115; and postoperative day 7, 0.0430 +/- 0.0115 mg/kg per minute) and membrane-particle constant (postoperative day 3, 0.717 +/- 0.169 mg/kg) significantly increased postoperatively in comparison with preoperative values. These results indicate that the total capacity of the RES is augmented but that its functional phagocytic efficiency is diminished after abdominal surgery. This phenomenon is considered to be one of the immunological alterations caused by surgical stress. The chondroitin sulfate iron colloid test can be applied to monitor the dynamic change of the RES function under various conditions.

Establishment of a multi-dose study of chondroitin sulfate iron colloid for evaluation of the reticuloendothelial system function

The assay system of chondroitin sulfate iron colloid (CSFe) was established to evaluate the reticuloendothelial system (RES) function in individual rabbits. In the multi-dose study of CSFe, CSFe was repeatedly administered to each individual rabbit with increasing doses (0.6, 1.2, 2.4, 6.0 mg/kg) at set intervals. Blood samples were serially collected after injection of CSFe and the concentration of CSFe in serum was directly measured as an iron concentration by modifying the previously described assay method [1] to minimize the sample volume. The clearance rate of CSFe at each injected dose was computed by the least-squares method and the double-reciprocal plotting of the doses against the phagocytic velocities by the Lineweaver-Burk method was obtained in each rabbit. The maximum phagocytic velocity ( V max) and the CSFe concentration producing 1 2 V max ( K p) obtained in ten rabbits were 0.129 ± 0.025 mg/kg per min and 0.417 ± 0.121 mg/kg (mean ± S.D.), respectively. The results obtained from this multi-dose study were comparable to our previous results obtained from the mean values of five groups given different doses [1]. The clearance rates of CSFe (0.6, 1.2, 6 mg/kg) decreased after the co-injection of 80 mg/kg of carbon colloid. The calculated V max and K p in 29 rabbits were 0.125 mg/kg per min and 1.167 mg/kg. The K p was apparently greater than that of the control ( V max = 0.128 mg/kg per min, K p = 0.421 mg/kg). Carbon colloid (80 mg/kg) was injected to six rabbits after the completion of the first multi-dose study of CSFe and then the second multi-dose study of CSFe was repeated after 24 h. No differences were found in V max and K p between the two studies as were in the control group (10 rabbits) where saline was injected instead of carbon colloid. These results indicated that carbon colloid (80 mg/kg) gives a competitive and reversible inhibition on the RES. This multi-dose study of CSFe may be applicable for a bed-side analysis of the RES function in a patient.

肝腫ように対するＭＲＩ造影剤としてのコンドロイチン硫酸鉄コロイドの臨床応用の検討

肝腫ように対するＭＲＩ造影剤としてのコンドロイチン硫酸鉄コロイドの臨床応用の検討

Evaluation of the reticuloendothelial system function by the vascular clearance of chondroitin sulfate iron colloid

Vascular clearance of chondroitin sulfate iron colloid (CSFe) was evaluated as a test for the reticuloendothelial system (RES) in rabbits. Injected CS 59Fe was taken up by the RES in the liver (49%) and bone marrow (41%) after 60 min, suggesting its application for the RES function test. The clearance rate (K-value) of CSFe from the blood was calculated by measuring serum Fe concentrations after releasing iron from CSFe at certain intervals after injection. Depending upon different injected doses K-values were varied and the phagocytic velocity, computed by multiplying K-values by coprresponding injected doses, reached a plateau at high doses, indicating the phagocytosis of CSFe by the RES takes a saturation process. Double-reciprocal plotting of the dose and the phagocytic velocity showed a linear relationship, which provided the data on the maximum phagocytic velocity ( V max), 0.122 mg/kg/min, and the CSFe concentration producing 1/2 V max ( K p), 0.426 mg/kg. Thus, this CSFe clearance test can be used for the evaluation of the RES function.